Recent advances in hormonal contraception malini

Jan 19th Dr. K.V. Malini, Professor, BMC & RI,
RECENT ADVANCES IN
HORMONAL CONTRACEPTION
By
Dr. K. V. Malini
M.D., DGO.,MICOG,PGDMLE
PROFESSOR
Department of Obstetrics & Gynaecology
Bangalore Medical College & Research Institute
BENGALURU

Current population of the world - 6.5 billion
By 2050 - 9.1 billion
Census 2001 data - TFR - 3.04
NPP 2000 goal - ↓TFR to 2.1 by 2010
Clear relation between
TFR- contraceptive prevalence rate
Practice of contraception - very old
H/O fertility control - travels back to 4000 yrs
No safe & effective contraception until beginning of 20th century

First birth control pill with hormones - By Pincus & Rock in 1955
First hormonal contraceptive pill
Enovid Approved by FDA in1960
(150 µg Mestranol + 9.85mg norethynodrel)
Wide variety of hormonal contraceptives since available
In the evolution of OCs to their current form - two remarkable changes
over 4 decades
First change - to reduce E & P
Subsequent changes- Newer Progestins to decrese
androgenic effects

More recently :
Improvements in existing hormonal contraceptives
P containing IUDs - LNG –IUS
3 monthly P injection - monthly E+P Injection
Hormone releasing implant system
from multiple rods - fewer / Single rod
Development of novel delivery systems of
contraceptive Steroids:
Tran dermal patches
Vaginal rings

Innovations in oral contraceptives
COCs - currently used by 100 million women in the world
-WHO1998
Two changes:
Decrease in estrogen content-
150 µg of mestranol - 50µg 0f EE- 30µg of EE-20µgof EE in 2000.
Low dose pills - same efficacy
same level of contraception
comparable cycle control
reduced bloating and breast tenderness
low risk of VTE, stroke & MI
- Contraception1999;60: 321-329
PR with 20µg OC pill- 0.07-2.1/ 100WY
- Fertil Steril 2001;75: 457-465

Contraceptive progestogens - classified according to structure
All have steroid skeleton with 4 rings
Categorized into 3 tetracyclic structures
-Pregnanes
-Estranes
-Gonanes
Preganes- derived from P molecule
Derivatives of 17α (OH)P acetate Derivatives of (OH ) P acetate
 MPA
 Acetates of Megestrol
 Chlormedinone
 Cyproterone
 Hybrid P-nonpregnanes & drosperinone
( combine structural elements of other progestogens or chemical
groups)

Estranes:
First generation P - derived from ethisterone
Removal of carbon at C-19 position-progestational & residual
androgenic activity
Referred to as 19-Nortestosterone
Includes: Norethindrone, N-aceatate, E. diacetate,
lynoestrenol & norethynodrel
Dienogest( Hybrid P) -derived from norethisterone
No androgenic activity, lesser effect on glucocorticoids

Gonanes:
2nd
generation P - LNG& NG (developed in 1970s)
3rd
generation P - desogestrel, gestodene, norgestimate
( developed in 1980s)
Gonane structure lacks both C-18 & C-19 angular methyl radicals
LNG & dlNG - derivatives of 13 ethyl gonanes
More active progestational agents than estranes
2nd
generation P - more androgenic
3rd
generation P - minimal impact on lipid profile
& plasma insulin concentration

Newer pills
Pills with Drosperinone:
DRSP- unique P derived from 17α spironolactone
3 mg of DRSP = 25 mg of spironolactone
Pharmacological profile - identical to natural P
↓ salt & water retention but ↑K retention
↓body weight, both systolic & diastolic BP
Anti androgenic activity – 30% of that of CA
- climacteric 2005;suppl 3: 4-12
DRSP is as effective as CA for mild to moderate acne
-Gynecol Endocrinol 2007;23:38-44
Relieves premenstrual dysphoric disorder
-obstet.gynecol 2005;106:492-497
Adverse CVS & other serious effects - similar to other COCs
Risk of VTE - similar to OCP with 3rd
generation P

COCs -30 µg EE+3mg of DRSP -Yasmin (ScheringAG, Germany)
Approved by FDA in 2001
22 clinical trials in Europe & USA
Results of European 13 cycle trial
Symptoms EE/DRSP EE/DSG
Intermenstrual bleeding 21% 23.9%
Head ache 9.8% 6.3%
Breast pain 6.4% 4.6%
Nausea 4.2% 1.7%
Abdominal Pain 2.2% 2.2%
Migraine 2.1% 2.4%
-Eur.Jl contracept, Reprod. Health care 2000;5:25-35
Pearl Index = 0.55/100WY

Disadvantage - Hyperkalemia
Not be used in women with renal , hepatic & adrenal disorders
Consider medical & drug history – before prescribing DRSP /OCP
Drugs that increase serum potassium
 ACE inhibitors
 Angiotensin receptor antagonists
 K- sparing diuretics
 Heparin
 Aldosterone antagonists
 NSAIDs
Have serum potassium level checked during 1st
Rx cycle
-Med lett 2002;44:55-7
Low hormone version - 20µgEE + 3mg DRSP (Yasminelle-Bayer
Schering Pharma ) has been launched

Pill with Dienogest
Dienogest - 19 nortestosterone derivative
Also called Hybrid P
The only nortestosterone derivative that has cyanomethyl
instead of ethinyl group at C-17
COC : EE 30µg + 2mg of dienogest
(Valette, Jenopharm Gmb H Co.)
Has limited market – mainly in Central Europe

Pill with Cyproterene acetate
35µg EE + 2mg of CA
CA: Synthetic P derived from 17α-OH progestogen
Has antigonadotrophic & peripheral antiandrogenic activity
MOA:
 Inhibits T& DHT action by binding competitively to
intracellular receptors
 Antigonadotrophic -↓ ovarian androgen synthesis
 ↓5α reductase activity
 ↑ testosterone clearance

Study conducted in Italy in 2001- effect of long term
treatment(60 cycles) with EE+ CA in women with PCOS
 clinically acne disappeared in all within 12 – 24 cycles
 mild to moderate hirsutism disappeared in 36 -60 cycles
 severe hirsutism substantially decreased
 ovarian vol ,microcyst no & stromal % substantially decreased
 after 6 mths from end of therapy acne & hirsutism reappeared
- Human Reproduction vol 2001;16(1):36-42

Advantages:
 Safe & reliable
 Excellent cycle & endometrial control
 Additional benefit on hirsutism & acne
 Control of PCOS
 High psychological motivation due to its effect on androgenic skin
disorders
 Favorable effect on lipid & CHO metabolism
Disadvantages:
 Side effects similar to other COCs
 Risk of VTE similar to COCs with 3rd
generation P
- NZ Med J 2004;117(1206);u1176

Pill with extended cycle length
Introduced to suppress menstrual cycles with PMS& heavy bleeding
Approved by FDA in Sept 2003
Monophasic with EE 30µg+LNG 150µg
84 days followed by 7days of placebo
Suitable for women intend to have fewer cycles
Beneficial for women with medical problems
worsened by menstruation or adverse symptoms
caused by menstruation

Phase III clinicl trial – multicentric , parallel, RCT
47 study sites, 682 women-13 cycles
Results:
Extended pill Conventional pill
No of bleeding days 35 53
% of bleeding days 5.7% 12.2%
Discontinuation for
Unacceptable bleeding 7.7% 1.8%
PR 0.9% 1.3%
- Treat Endocrinol. 2005;4(3): 130-145
In 2006 Cochrane data base published analysis of 6 studies
Results were similar in both the groups

Conditions benefited from extended pill:
Dysmenorrhoea Catamenial seizures
Menorrhagia Asthma attack
Iron deficiency anemia Rheumatoid arthritis
Endometriosis Bechet’s syndrome
PMS Coagulopathies
Menstrual migraine- 7% Patients on anticoagulant therapy
Additional Benefits:
• Significant societal & patient savings
• Cost savings – greatest for women with heavy menses
• High patient compliance

Emergency contraception
LNG 0.75mg 2 tabs 12 hrs apart
WHO multicentric RCT:
Single dose of 1.5mg of LNG- as effective
as 2 doses given 12 hrs apart up to
120 hrs of exposure
-Lancet 2002;360:1803-1810
RU486:
 Competes with P for receptor binding
 Alters ovarian follicle maturation ,ovulation
 Accelerates tubal transportation of embryo & alters fertilization
 Interferes with implantation

Studies comparing 10 mg of Mifepristone with LNG :–
PR 1.5% - similar to LNG
- Lancet 2002;360:1803-1810
Another study - 635 women – PR 1.1%
-Eur Jl contraception,Reproductive Health Care2007;12:162-167
Though LNG - IUS can be used as EC- no study trial to show that it is
effective
Emergency help line - Ph. no 39700111
Slogan is : “NUMBER LAGAO , UPAYE PAO”

Progesterone only pill
Described 4 decades ago - introduced recently
Acts by:
 Producing cervical mucus changes
 Endometrial alterations
 Always endometrium in wrong phase of development
 Accelerated tubal motility
 Disturbed CL function
 Inhibition of ovulation - traditional POP - 40-50%
- desogestrel - 97% of cycles
Indian trial with desogestrel pill :
408 women over 150 months – pearl index of 0.2 / 100 WY
- Obstet Gynaecol Today 2003;1:8(3)

How to initiate ?
Regular cycles - start from 5th
day - WHO recommendation
Amenorrhoea - R/O pregnancy
- with additional contraception or if abstinence of sex for
48 hours – anytime
During lactation :
Any time 6wks to 6 mths post partum (if EBF)
> 6wks - if menstruating on 5th
day
Not breast feeding - immediately after birth and any time within 6wks
Timing of administration - with desogestrel not considered missed if
delayed by 12 hrs or less.
Cerazette -75µg of desogestrel x 28
- Contraception 2003;71:8-13

Improved existing Methods
Injectable contraceptive :
Monthly injectable Lunelle - MPA 25mg + 5mg of EC
FR - 0.1-1/100 WY
Availability - aqueous suspension of microcrystals in vial
Administration - deep IM on deltoid or gluteal region
WHO recommendation - 30 + / - 3 days or once a mth
Initiation - 5th
day of menses
- immediately after I & II tri-abortion
After delivery - if not lactating - within 3 wks.
- if lactating - after 6 months

MOA : Same as COCs
CI & efficacy: same
WHO sponsored multicentric trial outside US - PR 0-2/100WY
-Contraception1988;37:1-20
Phase III b trial performed in US - similar results
No studies to provide information about non-contraceptive benefit
-Contraception1999;60:179-87
Advantage over P only injectable :
 More rapid return to fertility on discontinuation (63 – 112 days)
 Improved bleeding pattern
 No effect on BMD
Disadvantages:
Too frequent injections

LNG – IUS
Most popular, long term, reversible form of contraception
Releases 25 µg of LNG / day x 5 yrs
Inserted within 5 days of menses
NSAID / Paracervical block /
mesoprostol 200-400 µg recommended
Population council - RT :
FR - 1.1/100 WY
10 yr FR for sterilization – 1.9 / 100 WY
- Contraception 1999;44:473/482

Adverse effects:
Altered bleeding patterns
Spotting or bleeding in the initial 3 to 6 mths
Later reduction of MBL by 80% at 3 mths
95% at12 mths
20 – 50% become amenorrheic within first 2 yrs
- Contraception 2002;65:129-32
Advantages:
Following removal - rapid return to fertility
With 1 yr life table PR of 89 / 100 WY < 30 yrs of age
- Am Jl Obstet Gynaecol 1992;166:1208 – 13

MOA:
Mainly on cervical mucous
Local supression of endometrium
Stimulates glycodelin - A in the endometrium which inactivates sperms
Contra indications:
 Evidence of PID, vaginitis, Cervicitis
 Submucous fibroids / fibroids distorting cavity
 Uterine Anomaly
 Pregnancy
 Undiagnosed vaginal bleeding
 Genital malignancies

Hormone releasing implant system
Has been available for several years
Recent improvement in technology
 delivery of an effective dose of steroids
 use of fewer implants
 less androgenic steroids
Implanon (Organon) :
Single rod 40mm x 2mm
Releases etonogestrel at an initial rate of 60µg / day
Made up of ethylene vinyl acetate co polymer
Effective for 3yrs
No pregnancies reported
- Contraception1999;60:1-8
Implanon not yet available

Norplant II :
2 rods – 4cm length
150 mg of LNG / 3 yrs
FR : 0.8 – 1 / 100 WY
Approved by FDA but not yet marketed in US
Newer implants:
Biodegradable P implants in the form of rods / pellets effective
for 1 yr under development
- Reprod. Med. 2001;19:339-54
Male contraceptive implants:
SC testosterone pellets + desogestrel pill daily
4 LNG implants followed 4 wks later by 1000mg of TU IM every
8 wks x 24wks under trial

Novel Delivery system
Contraceptive vaginal ring
Made up of flexible ethylene vinyl acetate copolymer-2 inches in
diameter
Releases etonogestrel 120 µg + EE 15µg / day
Initiated within 5 days of menses
Used for 3 wks, removed for 1 wk
Absorption through vag epithelium - efficient and rapid
User controlled with easy insertion and removal
Open label RT – 45 women Nuva Ring( Organon)
Results:
Effective and reversible method – FR: 0.65 / 100 WY
- Human Reproduction Vol 17(10) Oct 2002

Transdelivery system of steroids via patch
Contraceptive patch approved by FDA in 2002
Applied once weekly x 3 wks with 1 patch free wk
Releases 150µg of Norelgestromin (active M of norgestimate) + 20µg
of EE / day
Sustained release system
Effective serum concentration 4x5cm=20cm2
Serum concentration not affected by heat, humidity, exercise or cold
water immersion
FR: 0.8 / 100 WY
Higher in women with body wt > 90kg
- Fertil Steril 2002; 77:suppl(2) S 3-12
Ortho - Evra

Open label, 73 centers study of 1672 healthy, sexually active women
for 6 to13 cycles
Results:
Method failure : 0.7%
FR : 0.4%
Perfect compliance : 90%
Detachment of patch : 1.9%
Application site reaction : 1.9%
Nausea : 1.8%
Emotional lability : 1.5%
Headache : 1.1%
Breast discomfort : 1%
- Obstet Gynaecol 2001; 98 : 799 - 805

MALE HORMONAL CONTRACEPTIVES
Development of male hormonal contraceptives-interesting and
challenging area of research
Problems:
 Safety and efficacy concerns
 Response- variable -90% Chinese
- 60% Caucasians
- 5-20% nonresponders
 High doses required to suppress gonadotrophins
 Effect on other organs like liver, muscle, bone, and brain, decrease in
HDL
 Additional contraceptive for 3 months
 Expensive when compared to other male methods or female methods
Lack of trust among women
 Delayed return to fertility
Poor acceptance among men

Study conducted in Australia -55 men
T implants -replaced every 4 months
P injections - given every 3 months
Results: None of the partners conceived
Reversible
Maintain male sexual health
published in Jl of clinical endocrinology & metabolism
- BBC news Monday 6th Oct 2003 GMT13.30 UK
Larger and longer trials are required
May take few years for it to become available

Chris Harris, Sydney Policeman

Recent advances in hormonal contraception malini

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